A number of pharmaceutical agents and potential pharmaceutical agents suffer from poor aqueous solubility, which can hamper the development of suitable clinical formulations. One approach to solving this problem is by synthesizing new derivatives with more polar functionality to increase water solubility. However, the addition of polar functionality is often disadvantageous when the therapeutic agent is required to cross a membrane for activity.
Another approach to increasing water solubility is to synthesize prodrugs in which the therapeutic agent is conjugated to a carrier group which assists in solubilizing the therapeutic agent and which is then cleaved in situ to regenerate the therapeutic agent which is now better able to penetrate a given membrane.
More recently, new methods of formulating compounds have become available. In particular, formulations based on liposome technology are now of significant interest. Liposomes are vesicles comprised of concentrically ordered phospholipid bilayers which encapsulate an aqueous phase. They form spontaneously when phospholipids are exposed to aqueous solutions and can accommodate a variety of bioactive molecules. Liposomes have been used for the selective delivery of both pharmaceutical agents and imaging agents. Nevertheless, a number of pharmaceutical agents have proven difficult to formulate, even in liposomes.
Paclitaxel (Taxol.RTM.), compound 1, is a diterpene isolated from the bark of the Western (Pacific) yew, Taxus brevifolia and is representative of a new class of therapeutic agent having a taxane ring system. Paclitaxel and its analogs have been produced by partial synthesis from 10-deacetylbaccatin III, a precursor obtained from yew needles and twigs, and by total synthesis. See Holton, et al., J. Am. Chem. Soc. 116:1597-1601 (1994) and Nicolaou, et al., Nature 367:630 (1994). Paclitaxel has been demonstrated to possess antineoplastic activity. More recently, it has demonstrated efficacy in several human tumors in clinical trials. See McGuire, et al., Ann. Int. Med., 111:273-279 (1989); Holmes, et al., J. Natl. Cancer Inst., 83:1797-1805 (1991); Kohn et al., J. Natl. Cancer Inst., 86:18-24 (1994); and Kohn, et al., American Society for Clinical Oncology, 12 (1993). ##STR1##
Taxol has proven difficult to formulate for therapeutic administration. Efforts to address the formulation problem have focused on synthesis of prodrugs and water-soluble analogs. See, Deutsch, et al., J. Med. Chem. 32:788-792 (1989), Nicolaou, et al., Nature 364:464-466 (1993) and Methew, et al., J. Med. Chem. 35:145-151 (1992). Attempts at liposomal formulations have also been difficult. See, Sharma, et al., Cancer Res. 53:5877-5881 (1993). Other classes of therapeutic agents suffer similar drawbacks. In particular, the family of podophyllotoxins, of which 2 is representative have also proven difficult to formulate. ##STR2##
Still other classes of therapeutic agents, such as the daunomycin family of antibiotics (of which doxorubicin, 3, is representative) have been studied in liposomal formulations, but are hampered by such problems as limited affinity for the lipid bilayers. This results in compounds which are encapsulated entirely in the aqueous space and often have a tendency to leak out of the intraliposomal aqueous space.
What is needed are compounds which are designed for incorporation into the lipid bilayer and which can be easily formulated into liposomes and micelles. Moreover, the compounds should also act as prodrugs and ultimately result in a therapeutic agent which is free of any added functionality. Preferably, the approaches to the preparation of such compounds should have broad applicability to many classes of pharmaceutical agents.
Surprisingly, the present invention provides such compounds.